北京协和医院妇产科教授潘凌亚等发现，Annexin A3可能为卵巢癌铂类耐药标记蛋白。这项成果发表在2月15日出版的美国癌症研究协会（AACR）权威杂志《癌症研究》（Cancer Research）上，这一发现还于2009年12月份获得了国家知识产权局颁布的发明专利证书。
“卵巢癌耐药相关蛋白的比较蛋白组分析、筛选耐药标记物的研究”课题组以临床应用为导向，首先采用比较蛋白质组学技术，对多个铂类敏感和耐药的细胞系进行比较蛋白质组分析，寻找耐药相关的差异表达蛋白；发现了Annexin A3蛋白在全部5种卵巢癌铂类耐药细胞株中的表达明显升高，同时在mRNA和蛋白质的表达水平得到验证。
在进一步的临床标本的验证中，选取了40位卵巢癌化疗患者作为研究对象，其中20例对顺铂类药物敏感，另外20例对顺铂耐药。经过免疫组化检测发现，Annexin A3在临床卵巢癌铂类耐药患者的组织中表达明显升高，且Annexin A3高表达组的无瘤生存期显著缩短。研究揭示了Annexin A3是通过降低细胞内铂含量及铂-DNA结合量、降低卵巢癌细胞P53水平而产生耐药机制的。
动物实验也表明，Annexin A3高表达的细胞受顺铂作用后，其成瘤率明显上升。
该研究还发现，Annexin A3高表达的细胞对铂类药物的耐药性明显增强，但与紫杉醇、表阿霉素等药物无交叉耐药性，提示Annexin A3蛋白可能成为卵巢癌特异性的铂类耐药相关蛋白。
2003年以来，受北京协和医院重点基金资助，潘凌亚领导的课题组先后对卵巢癌耐药细胞系的培养诱导、卵巢癌化疗药物敏感及耐药细胞系进行蛋白质组学分析，研究成果陆续发表在《蛋白质组研究杂志》（J Proteome Res）、《肿瘤报告》（Oncol Rep）等期刊上，累计影响因子14.72。
Annexin是一组结构功能相似的Ca2+依赖磷脂结合蛋白，目前已拥有13个家族成员。Annexin A3在多种生物学活动中发挥作用，但较少被研究，Annexin A3蛋白表达与肿瘤的关系一直未见报道。近3年来，随着比较蛋白质组学技术的发展，逐渐出现了关于Annexin A3在肿瘤组织中表达的上调或下调的报道。协和医院妇产科的上述研究，是国际上首次关于Annexin A3与卵巢癌化疗耐药相关性的报道。
潘凌亚介绍说，卵巢癌是死亡率很高的一种妇科恶性肿瘤，化疗耐药是死亡的主要原因之一。北京协和医院关于Annexin A3可能为卵巢癌铂类耐药标记蛋白的发现，提示Annexin A3蛋白有望成为卵巢癌患者耐药的筛选标记物，同时提示医生对卵巢癌耐药患者的化疗方案进行选择。
更多阅读
《癌症研究》发表论文摘要（英文）
Cancer Research 70, 1616, February 15, 2010. Published Online First January 26, 2010;
doi: 10.1158/0008-5472.CAN-09-3215
Therapeutics, Targets, and Chemical Biology
Increased Expression of Annexin A3 Is a Mechanism of Platinum Resistance in Ovarian Cancer
Xuedong Yan1, Jie Yin1, Huiyu Yao2, Ning Mao2, Yili Yang3 and Lingya Pan1
Authors' Affiliations: 1 Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; 2 Department of Cell Biology, Institute of Basic Medical Sciences, Beijing, People's Republic of China; and 3 Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, Maryland
Corresponding Author: Lingya Pan, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuai Fu Yuan, Wang Fu Jing Street, Beijing 100730, China. Phone: 86-10-65296218; Fax: 86-10-65124875; E-mail: lingyapan@hotmail.com.
Resistance to platinum drugs has emerged as a major obstacle in the treatment of ovarian cancers. Through proteomic analysis, we have found that the expression of annexin A3, a member of the Ca2+ and phospholipid-binding annexin family, is significantly increased in platinum-resistant ovarian cell lines. Anti–annexin A3 immunostaining indicated that cancers from platinum-resistant patients also possess higher levels of annexin A3 than those from platinum-sensitive patients. Although expression of annexin A3 made susceptible ovarian cancer cells more resistant to platinum, expression of antisense annexin A3 downregulated its expression and rendered the resistant cells more sensitive to platinum. In athymic mice, the growth of tumors from inoculated SKOV3 cells was inhibited by the administration of platinum, whereas tumors from annexin A3–expressing SKOV3/Ann were resistant to platinum treatment. Interestingly, the intracellular platinum concentration and platinum-DNA binding are significantly lower in annexin A3–overexpressing cells than those in parental cells. The lower cisplatin concentration was also accompanied by reduced induction of p53, which could be restored by downregulation of annexin A3. These results indicate that increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer. It seems to act by preventing uptake or accumulation of platinum in cells. Therefore, it is conceivable that annexin A3 could be a target for therapeutic intervention and may also serve as a biomarker for drug resistance in ovarian cancer patients. Cancer Res; 70(4); 1616–24
Key Words: Ovarian cancer " drug resistance " annexin A3 " platinum
